This invention relates to treatment of neoplastic cells using viruses.
Cancer is a disease of highly evolved multi-cellular organisms. The disease is best defined by the four characteristics which describe how cancer cells act differently from their normal counterpart. First, in most cases, cancer originates from a single cell which proliferates to form a clone of malignant cells. Second, cancer cells grow autonomously and are not properly regulated by the normal biochemical and physical influences in the cells environment. Third, cancer cells are anaplastic which is the lack of normal coordinated cell differentiation. Fourth, cancer cells develop the capacity for discontinuous growth and dissemination to other body parts which is called metastasis.
The terms cancer, neoplasia and malignancy usually are used interchangeably. The term cancer refers to the full spectrum of malignant neoplasms, of which there are over a hundred known types to affect humans (See Mendelsohn, J., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 421-431). These can be broadly classified into three major types. Malignant neoplasms arising from epithelial structures are called carcinomas and constitute the vast majority of all malignant tumors. Malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas, and malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system, are called leukemias and lymphomas. A tumor is the neoplastic growth of the disease cancer.
Neoplasia is a process by which the normal controlling mechanisms that regulate cell growth and differentiation are impaired resulting in progressive growth. During neoplasia, there is a characteristic failure to control cell turnover and growth. This lack of control causes a tumor to grow progressively, enlarging and occupying spaces in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites, the tumor will likely cause death of the individual.
One-third of all individuals in the United States will develop cancer (American Cancer Society Yearly Outlook for 1990). The five year survival rate for these patients has risen to nearly 50% as a result of progress and early diagnosis and therapy of the disease (American Cancer Society Yearly Outlook for 1990). However, cancer remains second only to cardiac disease as a cause of death in this country (American Cancer Society Yearly Outlook for 1990). Nearly 20% of all Americans who die this year will die of cancer (American Cancer Society Yearly Outlook for 1990). Half of these deaths will be due to the three most common types of cancer: lung, breast, and colon.
Recently there has been a rapid expansion of cancer treatments. Even though new treatments are being developed, the need still exists for improved methods for the treatment of most types of cancers.
The preferential killing of cancer cells without deleterious effect on normal cells is the desired goal in cancer therapy. In the past this has been accomplished using a variety of procedures. These procedures include the administration of chemicals, chemotherapy, radiation, radiotherapy, and surgery.
Radiotherapy is a regional form of treatment used for the control of localized cancers (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446). Radiotherapy relies on the fact that some malignant diseases are more susceptible to damage by radiation. This difference in susceptibility depends on normal cells having a higher capacity for intercellular repair than neoplastic cells and the ability of normal organs to continue to function well if they are only segmentally damaged. If surrounding tissue can tolerate twice the radiation dose of a given tumor, then the tumor is radiosensitive. On the other hand, some tumors cannot be treated with radiotherapy. Cancer which extensively involves both lungs cannot be treated effectively with radiation therapy because of the greater radiosensitivity of the surrounding lung tissue (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446).
A more modern approach to the use of radiotherapy involves the use of chemicals as radiosensitizers. Chemicals such as n-ethylmaleimide or a synthesis blocker like buthionine sulfoximine can render cells radio sensitive and hence more susceptible to killing by radiation. These chemicals are in the early phases of development are not yet commercially available (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446).
Surgery is still considered the primary treatment for most early cancers (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446). However, most tumors are operable but not fully resectable. Some tumors that appear resectable have micrometastatic disease outside the tumor field. This leads to a recurrence of the cancer close to the initial site of occurrence. Any cancer showing a level of metatastis effectively cannot be cured through surgery.
Other types of localized therapy (nonsystemic) have been explored. These include local hypothermia (Salcman et al., J. Neuro-Oncol. 1:225-236 (1983)), photodynamic therapy (Cheng et al., Surg. Neurol. 25:423-435 (1986)), and interstitial radiation (Gutin et al., J. Neurosurgery 67:864-873 (1987)). To date these therapies have been met with limited success.
Radiotherapy and surgery offer ways of reducing the tumor mass in specific regions of the body that are accessible through surgical techniques or high doses of radiotherapy. Neither is applicable to the destruction of widely disseminated or circulating tumor cells characteristically present in most patients with cancer. This is the stimulus of the development of systemic treatments of cancer such as chemotherapy.
Chemotherapy involves the administration of toxic compounds systemically to a patient (Chabner, B. A., ed., Pharmacologic Principles of Cancer Treatment, Philadelphia, Saunders (1982)). Since cancer cells are growing more rapidly than normal cells, toxic compounds are more cytotoxic to cells undergoing rapid division.
Drug, development for cancer began with the accidental identification of the lymphocytic activity of mustard gas used in World Wars I and II. Nitrogen mustard, an antitumor drug, is a derivative of mustard gas and was used to treat lymphomas in the 1940""s (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446). Most of the early patients treated with nitrogen mustard had subsequent relapses. This was followed by an overwhelming disappointment and skepticism that cancer could be successfully treated with drugs.
The next drug investigated for antitumor activity was methotrexate (See Devita, V. T., in Harrison""s Principles of Internal Medicine, ed. Braunwald et al., 1987, McGraw-Hill Inc., New York, p. 431-446). Methotrexate, an antimetabolite, was first used successfully against acute childhood leukemia. In some of the early cases where methotrexate was used, remission produced by the drug appeared permanent.
New compounds are constantly being generated and selected both by rational drug design and random screening. There are six major classes of antitumor drugs; alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics, endocrine agents, as well as some miscellaneous drugs (Myers, C. E., in Cancer: Principles and Practice of Oncology, 2d ed., V. T. De Vito et al. (eds.), Philadelphia, Lippincott, 1985, pp. 290-328).
The use of chemicals, even though widespread in use, has proved of limited effectiveness in treating most cancer types. A major limitation of current chemotherapy is that it is effective only against the most rapidly dividing tumor cells. An additional drawback to the use of cytotoxic agents for the treatment of cancer are their severe side effects. These include nausea, vomiting, CNS depression, localized pain, bone marrow depression, bleeding, renal damage, hypo and hyperglycemia and hypersensitivity reactions.
A more modern approach to chemotherapy is to direct the toxic agents to the cancer cells themselves. This has been accomplished experimentally by linking the chemotherapeutic agent to either antibodies or nontoxic molecules that have a higher affinity for the tumor cells than normal cells. These directed toxic therapies are still in an early clinical phase of development and are not commercially available.
Certain types of cancer, for example gliomas, which are the most common primary tumor arising in the human brain, defy the current modalities of treatment. Despite surgery, chemotherapy, and radiotherapy, glioblastoma, the most common of the gliomas is almost universally fatal (Schoenberg, B. S., xe2x80x9cThe epidemiology of nervous system tumors,xe2x80x9d in Oncology of the Nervous System, M. D. Walker, ed., Boston, Mass., Martinus Nijhoff (1983); Levin et al., xe2x80x9cNeoplasms of the Central Nervous System,xe2x80x9d Chapter 46, pp. 1557-1611, in Cancer: Principles and Practice of Oncology, vol. 2, 3rd ed., De Vita et al., eds., Philadelphia, Lippincott Press (1989)).
Malignant tumors of the nervous system are usually fatal, despite recent advances in neurosurgical technique, radiation therapy, and chemotherapy. In particular, high mortality rates persist in malignant medulloblastomas, malignant meningiomas and neurofibrosarcomas, as well as in malignant gliomas.
Therefore, a need exists for the development of a technique that will selectively destroy tumors of the nervous system while sparing normal cells. In general, such treatment could potentially be used universally for the selective destruction of all types of neoplastic cells.
Compositions and methods are provided for selectively killing neoplastic cells. The method involves infecting neoplastic cells with an altered virus which is capable of replication in neoplastic cells but spares surrounding non-neoplastic tissue. Upon viral infection, the virus destroys infected cells, generally by oncolysis and/or xenogenization.